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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study a new model of cerebral ischemia, based on a middle cerebral artery (MCA) thrombosis in rats is described. Furthermore, the effect of the novel plasminogen activator (SUN9216), a plasminogen-plasminogen activator chimera, comprising the fibrin kringle 1 domain of a plasminogen, and the two kringles, and the serine protease domains of wild-type tissue plasminogen activator (t-PA), including a modification of the mannose glycosylation site on the kringle 1 of t-PA (PK1de1FE1X), was studied in this model. In the newly described model of thrombotic cerebral ischemia, an occlusive thrombus occurred usually within 8 min in the MCA as a consequence of an endothelial injury subsequent to a photochemical reaction between a systemically administered photosensitive dye (rose bengal) and a transillumination of the MCA with a high-intensity green light with a wavelength of 540 nm. The study was quantitated by means of pathological examination of the MCA and the brain. A platelet-rich thrombus was observed in the MCA using electron microscopical analysis based on ion beam bombardment. At 24 hr after induction of the thrombus, the brain was removed from 13 control animals, nine coronal sections were stained from each brain with triphenyltetrazoliumchloride (TTC), and the ischemic area was quantitated. A constant area of infarction was observed in the cortex and the lateral part of the basal ganglia. In a second group (n = 8), at 1 or 8 weeks after induction of the thrombosis in the MCA, the coronal sections were stained with hematoxylin and eosin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A simple and reproducible cerebral thrombosis model in rats induced by a photochemical reaction and the effect of a plasminogen-plasminogen activator chimera in this model. 836 30

Stroke stands as the third leading cause of death. It makes great demands on patients, who must not only survive the complications of the acute stages, but must cope then with the great physical and economic costs of long-term disabilities. Therefore, there is urgent need to establish generally useful regimens for the acute treatment of ischaemic stroke. Three treatment approaches are based upon pathophysiologic concepts derived from experimental work with focal cerebral ischaemia. These include pharmacologic strategies for arterial recanalisation, inhibition of inflammatory processes and neural protection. Focal cerebral ischaemia secondary to occlusion of a brain-supplying artery initiates neuronal and microvascular events, and the simultaneous processes of inflammation which further injure tissue. The use of plasminogen activators to mediate thrombus and lysis in the acute setting has been shown to be clinically beneficial. Further work with arterial reperfusion strategies is under way. Early clinical studies with polymorphonuclear leukocyte-dependent endothelial adhesion receptor antagonists are being completed, but a strategy has yet to emerge. A large effort examining the potential efficacy of agents which may stabilise or protect neurons from ischaemic injury has shown promise in experimental models, and has been translated into clinical trials. Experimental work, and limited clinical experience, have indicated that: (a) the time window for intervention is important in limiting ischaemic and inflammatory injury, and for reducing the risk of haemorrhagic transformation; (b) putative neuroprotective strategies may potentially elongate the time interval for treatment; and (c) limitations from the adverse effects of plasminogen activators and of agents which beneficially affect neuronal dysfunction during ischaemia must yet be overcome. This review surveys pharmacological approaches currently undergoing evaluation which provide the goal of establishing effective strategies for the treatment of patients with acute cerebral ischaemia.
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PMID:Trends and future developments in the pharmacological treatment of acute ischaemic stroke. 921 Oct 77

Human lys-plasminogen and the corresponding formulation buffer were tested in a rat model of global cerebral ischemia (clamping of both carotid arteries, withdrawal of 5 ml blood for 30 min). The two main parameters, tested in different experimental set-ups, were 1. brain edema (water content) 23.5 h after reperfusion and 2. assessment of neurological deficits 24, 48 and 72 h after reperfusion. In some groups of animals of the first set-up, brains were examined histologically for microvascular fibrin deposits. In a separate group of animals the fibrinolytic plasma activity of rats treated with 500 CU/kg lys-plasminogen was studied. Concerning brain water content lys-plasminogen completely antagonized the formation of brain edema when given with 500 caseolytic Units (CU)/kg i.v. with blood reperfusion and was still effective when given 30 min later. 200 CU/kg i.v. given with blood reperfusion as well as 500 CU/kg i.v. given 60 min after blood reperfusion proved ineffective. In none of the brains investigated microvascular fibrin deposits were found. In experiments with assessment of neurological deficits, animals treated with 500 CU/kg lys-plasminogen i.v. showed almost no disabilities (like sham operated animals) when compared to ischemic (positive) controls which were rather severely handicapped. The formulation buffer of lys-plasminogen, tested in an equivalent volume, was without any effect in both set-ups. No fibrinolytic activity was found in plasma samples of rats up to 240 min after treatment with 500 CU/kg lys-plasminogen i.v. It is concluded from these experiments that human lys-plasminogen has a protective effect in rats against the sequelae of global cerebral ischemia which is not related to the well-known fibrinolytic potential but might be a separate quality.
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PMID:Studies on the effect of human lys-plasminogen in a rat model of global cerebral ischemia. 942 72

We analysed the results of coagulation studies in an unselected series of young adults with acute cerebral ischaemia. Our aims were (a) to determine the prevalence of coagulation disorders among these patients, (b) to investigate the relation between the presence of coagulation abnormalities and large vessel disease or potential sources of cardiac embolism and (c) to evaluate the occurrence of thrombotic events in patients with or without coagulation disorders. One hundred and twenty consecutively admitted patients (53 men, 67 women, median age 38 years, range 15-45) who presented with acute cerebral infarction (n = 89) or a transient ischaemic attack (n = 31) were evaluated. Diagnostic studies consisted of electrocardiography, echocardiography, duplex scanning, and/or angiography. Coagulation studies included activity tests of protein S, protein C, antithrombin, plasminogen, measurement of immunoglobulin G (IgG) anticardiolipin antibodies (ACLA), and a dilute prothrombin assay. Initially, 30 patients had increased ACLA titres and 28 had an abnormal dilute prothrombin assay, suggesting lupus anticoagulant. Decreased protein S, protein C and antithrombin activity were detected in 20, 3 and 3 patients, respectively, excluding patients in whom the abnormalities could be explained by the use of medication, by pregnancy or puerperium. We detected a decreased activity of plasminogen in 5 patients. The disorders could be confirmed by a second assessment in only 2 patients with a protein S deficiency, in none of the patients with a protein C or antithrombin deficiency and in 1 patient with plasminogen deficiency. However, the abnormalities persisted in 19 of 21 patients with increased anticardiolipin IgG titres and in 9 of 20 patients with lupus anticoagulant. A confirmed coagulation disorder was not associated with stroke type or vascular risk factors, but it was more common among patients with large vessel disease (odds ratio: 3.8, 95% confidence interval (CI): 1.1-12.8). Sixteen patients had a recurrent thromboembolic event, but the risk of recurrence was not increased among patients with a confirmed coagulation disorder. Our results suggest that idiopathic coagulation disorders are found in about a quarter of young stroke patients. They are difficult to predict and probably interact with other risk factors.
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PMID:Coagulation disorders in young adults with acute cerebral ischaemia. 945 24

Modeling of focal cerebral ischemia seeks to understand mechanisms of injury and to test agents as potential stroke therapies. However, modeling has been singularly unpredictable in ischemic cerebrovascular disease for a number of reasons related to the incompletely understood pathophysiology of ischemic stroke and to the characteristics of models prepared to mimic the clinical condition. The development of models of focal cerebral ischemia must take into account known species differences and idiosyncrasies, underlying vascular disease processes, the nature of thrombotic processes, cellular reactivities, the presence of co-stimulation (e.g., inflammation), the characteristics of immunologicals and reporter molecules, the coincident use of other pharmacologic modifiers (e.g., anesthesia), and stress. These elements are also potential contributors to cerebral tissue injury and its assessment but may affect other species differentially. On the other hand, study design issues have been shown to be particularly relevant to limiting development of some agents for clinical stroke treatment. Experience from experimental and clinical work on vascular active approaches (e.g., plasminogen activators) suggests that active dialogue regarding the relationships between clinical outcomes and outcomes in appropriate animal models is necessary. Success appears more likely when the model more closely matches the known human pathophysiology and the interventions applied in the models are definitely characterized in that species. Rather than moving directly to interventional studies in humans, the use of several appropriate animal models is encouraged where those models exist. Where not, careful consideration of study design and the biology of the disorder is a prerequisite.
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PMID:Clinical trials in acute stroke: why have they not been successful? 974 38

In focal cerebral ischemia the plasminogen-plasmin system plays a role in the fibrinolysis of vessel-occluding clots and also in the proteolysis of extracellular matrix components, which potentially contributes to brain edema and bleeding complications. The authors investigated the plasminogen activation after middle cerebral artery occlusion with and without reperfusion (reperfusion intervals 9 and 24 hours) in rats by histologic zymography and compared areas of increased plasminogen activation to areas of structural injury, which were detected immunohistochemically. After 3 hours of ischemia, increased plasminogen activation was observed in the ischemic hemisphere. The affected area measured 5.2%+/-8.5% and 19.4%+/-30.1% of the total basal ganglia and cortex area, respectively. Reperfusion for 9 hours after 3 hours of ischemia led to a significant expansion of plasminogen activation in the basal ganglia (68.8%+/-42.2%, P < 0.05) but not in the cortex (43.0%+/-34.6%, P = 0.394). In the basal ganglia, areas of increased plasminogen activation were related to areas of structural injury (r = 0.873, P < 0.001). No such correlation was found in the cortex (r = 0.299, P = 0.228). In this study, increased plasminogen activation was demonstrated early in focal cerebral ischemia. This activation may promote early secondary edema formation and also secondary hemorrhage after ischemic stroke.
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PMID:Plasminogen activation in focal cerebral ischemia and reperfusion. 1069 71

Polymorphonuclear leukocytes are activated in acute ischemic stroke. Activated polymorphonuclear leukocytes may contribute to thrombolysis by proteolytic degradation of fibrin and by modification of the plasminogen system. We used an in vitro thrombolysis model to investigate (1) thrombolytic properties of leukocytes in young and healthy subjects, (2) to test the hypothesis of increased polymorphonuclear leukocyte-associated thrombolysis in patients with acute cerebral ischemia, and (3) to assess plasminogen-dependent and -independent thrombolytic properties of polymorphonuclear leukocyte elastase. Coincubation of polymorphonuclear leukocytes with fibrin clots led to increased thrombolysis, a process reaching statistical significance after 8 hours [1x10(7) polymorphonuclear leukocytes/mL; 12.8+/-1.9% (mean+/-SEM), spontaneous clot lysis: 7.3+/-0.7%]. Polymorphonuclear leukocytes inside clots caused more efficient thrombolysis than polymorphonuclear leukocytes in the incubation medium. Spontaneous and polymorphonuclear leukocyte-associated lysis tended to be lower in patients with acute cerebral ischemia (n=9, 24 hours, 9.5+/-1.8% and 12.9+/-2.2%) than in age- and sex-matched control subjects (n=8; 12.2+/-2.0% and 17.4+/-1.9%). In the presence of alpha(2)-antiplasmin, thrombolysis tended to be faster with elastase-digested plasminogen (miniplasminogen) than with native plasminogen. Purified polymorphonuclear leukocyte elastase itself had no thrombolytic effect. We conclude that the thrombolytic capacity of polymorphonuclear leukocytes from peripheral blood is small and slow and may have been overestimated in previous reports. Polymorphonuclear leukocyte thrombolytic activity may not be increased in acute cerebral ischemia. Miniplasminogen may be an interesting adjunct to plasminogen activators in acute stroke models.
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PMID:Thrombolytic properties of leukocytes from peripheral blood in healthy subjects and in patients with acute cerebral ischemia. 1070 31

Thrombosis and ischaemia are often linked to an atherosclerotic arterial lesion. An inflammatory process implicating leucocytes and inflammation mediators (cytokines) as well as atheroma plaque rupture liberating tissue factor are at the origin of this pathology. Equally, blood platelets play an important role, not only with the formation of platelet aggregates, but also by their procoagulant action resulting from the exposure of membrane phospholipids. Apoptotic cells release procoagulant microparticles from the plaque, favouring thrombogenesis. In this context reperfusion would a priori restore blood flow, but it is also the origin of cytotoxicity due to the sudden release of necrotising factors. Various animal models are used to experimentally reproduce arterial thrombosis either following or not following ischaemia/reperfusion. Among them the model of progressive coronary occlusion by intraluminal electrical stimulation, the model of quasi-instantaneous thrombosis by the introduction of a copper coil, and the model of ischaemia/reperfusion by occlusion of the left descending coronary for 90 minutes followed by reperfusion have been studied more precisely in the dog. In the rat, cerebral ischaemia followed by reperfusion has been provoked with occlusion of the middle cerebral artery. The studies in dogs show that Enoxaparine significantly reduces the formation of coronary thrombus induced progressively by an anodal current and potentiates the action of the tissular activator plasminogen (t-PA) on a recently formed thrombus. At the level of myocardial ischaemia. Enoxaparine reduces the extent of infarction as well as the neutrophil and platelet accumulation in the infarcted zone or in at risk zone. This effect seems to correlate with an anti-inflammatory type action demonstrated elsewhere in vitro with platelet/neutrophil adhesion in the presence of P-Selectin. In all of these studies standard heparin used under the same conditions proves to be inactive. In the ischaemia/reperfusion model in the dog, aspirin has been shown to be ineffective up to a dose of 6 mg/Kg. Enoxaparine is an example of a possible double anti-thrombotic and anti-ischaemic component in the prevention of disorders caused by the thrombosis-ischaemia-reperfusion triad.
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PMID:[Thrombosis and ischemia: experimental data]. 1250 Jun 2

To determine if MRI can predict intracerebral plasminogen activation after focal cerebral ischemia (FCI), ischemic regions detected by MRI after 48 h of permanent FCI in rats were compared with areas of increased plasminogen activation, defined by histological zymography after 72 h of ischemia. The overlap between areas of MRI alterations (64.5% +/- 5.4% of total ischemic hemisphere) and areas with increased plasminogen activation (62.2% +/- 3.6%) was significant for the hemisphere (p < 0.001), the cortex (p < 0.05), and the basal ganglia (p < 0.05). Thus, MRI can predict the extent of increased plasminogen activation, which may play a role in BBB-mediated post-ischemic brain edema and secondary hemorrhage.
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PMID:MRI predicts area of increased plasminogen activation in permanent focal cerebral ischemia. 1250 Jul 7

Tissue plasminogen activator (tPA) is a serine protease that converts plasminogen to plasmin. It plays an important role in the nervous system, including the processes of neuronal migration, neurite outgrowth, and neuronal plasticity. tPA has also been suggested to have a role in several neuropathological conditions, such as cerebral ischemia, seizures, and demyelinating diseases. To investigate the role of tPA in spinal cord injury, wild-type mice and mice with homozygous tPA deficiency (tPA(-/-) mice) were subjected to spinal cord contusion and the differences of hindlimb function, electrophysiological changes, and histopathological changes were assessed for 6 weeks. Functional recovery was greater in tPA(-/-) mice than in wild-type mice throughout the observation period. The time course of myoelectric motor-evoked potentials supported the hindlimb functional findings. Histological examination showed that injured areas were smaller in tPA(-/-) mice than wild-type mice on Luxol fast blue staining or myelin basic protein and neurofilament protein immunostaining at 6 weeks after contusion. Electron microscopy showed that the white matter was better preserved in tPA(-/-) mice than in wild-type mice. The expression of tPA protein was widespread on the first day after contusion and this expression was detected for at least a week. Activation of microglia/macrophages and apoptotic cell death were significantly reduced in tPA(-/-) mice after contusion. This study shows that neural damage is decreased in tPA(-/-) mice after spinal cord injury. Suppression of tPA production may help to decrease secondary injury after spinal cord contusion.
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PMID:Decreased neural damage after spinal cord injury in tPA-deficient mice. 1261 87


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